Plasma Membrane Profiling Reveals Upregulation of ABCA1 by Infected Macrophages Leading to Restriction of Mycobacterial Growth.

The plasma membrane represents a critical interface between the internal and extracellular environments, and harbors multiple proteins key receptors and transporters that play important roles in restriction of intracellular infection. We applied plasma membrane profiling, a technique that combines quantitative mass spectrometry with selective cell surface aminooxy-biotinylation, to Bacille Calmette-Guérin (BCG)-infected THP-1 macrophages. We quantified 559 PM proteins in BCG-infected THP-1 cells. One significantly upregulated cell-surface protein was the cholesterol transporter ABCA1. We showed that ABCA1 was upregulated on the macrophage cell-surface following infection with pathogenic mycobacteria and knockdown of ABCA1 resulted in increased mycobacterial survival within macrophages, suggesting that it may be a novel mycobacterial host-restriction factor.Medical Research Council (Clinician Scientist Fellowship), Tsinghua University, Wellcome Trust (Senior Fellowship (Grant ID: 108070/Z/15/Z)), National Institute for Health Research (Academic Clinical Fellowship), China Scholarship CouncilThis is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fmicb.2016.0108

A 58-Year-Old Woman with Abdominal Symptoms and Elevated C-Reactive Protein

Babak Javid and colleagues discuss the differential diagnosis, investigation, and management of a woman with abdominal symptoms and a raised C-reactive protein

Drug-resistance mechanisms and tuberculosis drugs.

This publication presents independent research supported by the Health Innovation Challenge Fund (HICF-T5-342 and WT098600), a parallel funding partnership between the UK Department of Health and Wellcome Trust.This is the final version of the article. It first appeared at http://dx.doi.org/10.1016/S0140-6736(14)62450-8

Fever of Unknown Origin with Final Diagnosis of Imported Malaria: A Case Study

One of the most important infectious diseases in the world is Malaria. About half of the world populations are exposed to the risk of the disease. The program for controlling and eradication of Malaria has been being conducted in our country since many years ago. One of the public health problems in the endemic and non-endemic countries is Imported Malaria which can cause new and permanent infected foci. Population movement and travelling from endemic areas can transmit the disease to the clean areas and can also transmit the drug resistant Protozoa particularly Plasmodium Falciparum. Our case study describes a 30 year old person who has travelled to India for one month. He has visited a doctor in India because of fever, chills, malaise, and has received symptomatic treatment without any specific diagnosis .After returning to Iran, the symptoms appeared again after visiting by a doctor he has hospitalized with a diagnosis of Fever of unknown origin (FUO).He was checked for three days and on the fourth day, the blood smear of the patient showed Plasmodium Vivax. Ultimately he received the appropriate treatment and was discharged from the hospital in a good condition

A Comparative Evaluation of the Clinical Course, Laboratory Data and Chest CT scan Findings in Pediatric Patients with Covid-19 and Their Prognostic Value in Disease Outcome Estimation

Background: Most research on children and adolescents with COVID-19, had limited sample sizes and little clinical, laboratory, and radiological findings. The purpose of this research was to examine the features of children and adolescents with COVID-19 infection.Methods: This analytical retrospective study was conducted on children (1 to 12 years old) and adolescents (13 to 19 years old) with COVID-19 in Shahid Beheshti Hospital, Kashan, Iran. The data were then collected, entered into SPSS and analyzed.Results: In the adolescent group, the frequency of dyspnea (47.1 % vs. 11.9%), cough (67.1 % vs. 39.2%), lethargy (42.9 % vs. 25.9%), headache (35.7 % vs. 10.5%), myalgia (38.6 % vs. 14%), and chest pain (12.9 % vs. 0.7%) were significantly higher than those in children (p<0.05). Furthermore, in terms of laboratory findings, the normal range of neutrophils (13.8% vs. 1.4%), Cr (95% vs. 75.7%), and CRP (77.9% vs. 58%) were higher in children. Moreover, we found that the CT severity score among adolescent patients was significantly higher than that in children (4.84 ± 5.21 vs. 1.76 ± 3.25, p=0.006). Also, the frequency of consolidation (61.3 % vs. 19%), and ground-glass opacity (58.1 % vs. 28.6%) among adolescents were significantly higher compared to child cases (p<0.05) while only the frequency of mosaic pattern of pulmonary parenchymal attenuation was significantly higher among children (p=0.035).Conclusion: This research found milder clinical, biochemical, and radiological symptoms in children with COVID-19 than adolescents. However, radiological examinations showed greater rates of pulmonary parenchymal mosaic attenuation, which might help early diagnosis of COVID-19

dfrA thyA Double Deletion in para-Aminosalicylic Acid-Resistant Mycobacterium tuberculosis Beijing Strains.

This is the final version of the article. It first appeared from the American Society for Microbiology via http://dx.doi.org/10.1128/AAC.00253-16Para-aminosalicylic acid (PAS) is a group 4 anti-tuberculosis agent (1). It targets folate metabolism as shown in Fig. S1, which also summarises the known resistance mechanisms to this pro-drug (2). Recently, we reported a multidrug-resistant (MDR) Mycobacterium tuberculosis Beijing strain harbouring a deletion of both dfrA and thyA from Australia (Fig. 1A and Table S1) (3). Since then, we have found deletions affecting both genes in five further MDR Beijing strains (two isolated in Australia and three from Peru) and one extensively drug-resistant (XDR) Beijing strain from China. The Australian MDR strains were recovered from three patients with no apparent epidemiological links and were likely infected in their country of origin (Table S1). The three Peruvian isolates were closely related and consequently shared the same deletion, whereas the remaining strains were distantly related and had deletions that differed in size (Fig. 1A). Consequently, these five distinct deletions were acquired independently, which can be a signal for positive selection of resistance mechanisms. In line with this hypothesis, the strains from Australia and China were PAS resistant when tested with the BACTEC MGIT 960 system and on L?wenstein-Jensen medium, respectively (Supplementary Methods). Two out of the three Peruvian deletion mutants were also PAS resistant on 7H10 medium at 8 ?g/mL, whereas the two closely related ancestral wild-type strains were susceptible (Fig. 1B). We were unable to retest the strains at 2 ?g/mL, the recommended critical concentration by the Clinical and Laboratory Standards Institute and World Health Organization, which would have clarified whether the susceptible result for the third deletion mutant was an artefact (1, 4).This publication presents independent research supported by the Health Innovation Challenge Fund (HICF-T5-342 and WT098600), a parallel funding partnership between the UK Department of Health and Wellcome Trust, and grant SRG2015-00006-FHS from the University of Macau. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health, Public Health England, or the Wellcome Trust. M. E. T. is a Clinician Scientist Fellow funded by the Academy of Medical Sciences and the Health Foundation and the NIHR Cambridge Biomedical Research Centre. E.M. was supported by the Australian National Health and Medical Research Council?s Centre for Research Excellence in Tuberculosis. C. U. K. is a Junior Research Fellow at Wolfson College, Cambridge

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation